A general process for preparing allyl amines including (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane is described in U.S. Pat. No. 4,454,158, issued Jun. 12, 1984. A process for preparing (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane is described in International Application No. WO 93/24120, (PCT) published Dec. 9, 1993 and European Patent Application No. 0 295 604, published Dec. 21, 1988.
These methods, however, have the disadvantage that some of the steps to prepare a useful intermediate, (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol, use reagents and conditions that do not allow for economical, large scale, production of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol. Further, these methods use a phthalimide containing intermediate, the removal of which gives (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane contaminated with phthalhydrazide which is difficult to remove from the final product.
The process of the present invention for preparing (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane utilizes alkali metal salts of diformylamide. Generally, these salts are only partially soluble in useful solvents which causes the reaction rate to be surface area dependent.
The preparation and use of alkali metal salts of diformylamide has been described. J. N. Rakshit, J. Chem. Soc. 103, 1557-1562 (1913); E. Allenstein and V. Beyl, Chem. Ber. 100, 3551-3563 (1967); H. Yinglin and H. Hongwen, Synthesis 2, 122-124 (1990); and H. Yinglin and H. Hongwen, Synthesis 2, 615-618 (1990).
The methods for preparing alkali metal salts of diformylamide, however, have the disadvantage that the material is obtained as a solid mass. The solid obtained must be broken up which leads to material of differing and irregular particle size. Moreover, milling alkali metal salts of diformylamide to increase the surface area creates dust and inhalation problems. Further, the method of E. Allenstein and V. Beyl for preparing alkali metal salts of diformylamide, when carried out on large scale, gives material that is contaminated with detrimental amounts of methanol and ammonia.
An object of the present invention, therefore, is to provide novel methods for the economical preparation of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol which can be carried out without purification between steps.
Another object of the present invention is to provide a novel method for producing (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane utilizing intermediates which provide the final product without difficult to remove by-products.
Another object of the present invention is to provide a novel process for crystallizing alkali metal salts of diformylamide that gives alkali metal salts of diformylamide as a free flowing granular solid that is free of detrimental amounts of methanol and ammonia.
Another object of the present invention is to provide a novel crystalline form of sodium diformylamide.
A further object of the present invention is to provide novel intermediates useful for preparing (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane.